Collagen VI-related dystrophy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Collagen VI-related dystrophy is a group of disorders that affect skeletal muscles (which are the muscles used for movement) and connective tissue (which provides strength and flexibility to the skin, joints, and other structures throughout the body). Most affected individuals have muscle weakness and joint deformities called contractures that restrict movement of the affected joints and worsen over time. Researchers have described several forms of collagen VI-related dystrophy, which range in severity: Bethlem muscular dystrophy is the mildest, an intermediate form is moderate in severity, and Ullrich congenital muscular dystrophy is the most severe.

People with Bethlem muscular dystrophy usually have low muscle tone (hypotonia) in infancy. Muscle weakness can begin at any age but often appears in childhood to early adulthood. The muscle weakness is slowly progressive, with about two-thirds of affected individuals over age 50 needing walking assistance, particularly when outdoors. Affected individuals usually develop contractures by adulthood, typically in their fingers, elbows, shoulders, and ankles. Older individuals may develop weakness in respiratory muscles, which can cause breathing problems. Some people with this mild form of collagen VI-related dystrophy have skin abnormalities, including small bumps called follicular hyperkeratosis on the arms and legs; soft, velvety skin on the palms of the hands and soles of the feet; and abnormal wound healing that creates shallow scars.

The intermediate form of collagen VI-related dystrophy is characterized by muscle weakness that begins in infancy. Affected children are able to walk, although walking becomes increasingly difficult starting in early adulthood. They develop contractures in their fingers, elbows, shoulders, and ankles in childhood. In some affected people, the respiratory muscles are weakened, requiring people to use a machine to help them breathe (mechanical ventilation), particularly during sleep.

People with Ullrich congenital muscular dystrophy have severe muscle weakness beginning soon after birth. Some affected individuals are never able to walk and others can walk only with support. Those who can walk often lose the ability, usually in early adolescence. Individuals with Ullrich congenital muscular dystrophy develop contractures in their shoulders, elbows, hips, and knees, which further impair movement. Many individuals with this form of the condition have loose joints (joint laxity) in the fingers, wrists, toes, ankles, and other joints. Affected individuals need continuous mechanical ventilation to help them breathe while sleeping, and some may need it in the daytime. As in Bethlem muscular dystrophy, some people with Ullrich congenital muscular dystrophy have follicular hyperkeratosis; soft, velvety skin on the palms and soles; and abnormal wound healing.

Individuals with collagen VI-related dystrophy often have signs and symptoms of multiple forms of this condition, so it can be difficult to assign a specific diagnosis. The overlap in disease features, in addition to their common cause, is why these once separate conditions are now considered part of the same disease spectrum.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also known as mutations) in the COL6A1, COL6A2, and COL6A3 genes can cause the various forms of collagen VI-related dystrophy. These genes each provide instructions for making one component of a protein called type VI collagen. Type VI collagen makes up part of the extracellular matrix that surrounds muscle cells and connective tissue. This matrix is an intricate lattice that forms in the space between cells and provides structural support. The extracellular matrix is necessary for cell stability and growth. Research suggests that type VI collagen helps secure and organize the extracellular matrix by linking the matrix to the cells it surrounds.

Variants in the COL6A1, COL6A2, and COL6A3 genes result in a decrease or lack of type VI collagen or the production of abnormal type VI collagen. While it is difficult to predict which type of variant will lead to which form of collagen VI-related dystrophy, in general, lower amounts of type VI collagen lead to more severe signs and symptoms that begin earlier in life.

Changes in type VI collagen structure or production lead to an unstable extracellular matrix that is no longer attached to cells. As a result, the stability of the surrounding muscle cells and connective tissue progressively declines, which leads to the muscle weakness, contractures, and other signs and symptoms of collagen VI-related dystrophy.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Collagen VI-related dystrophy is often inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Bethlem muscular dystrophy is typically inherited in an autosomal dominant manner. The affected person usually inherits the variant from one affected parent. The intermediate form and Ullrich congenital muscular dystrophy can also follow an autosomal dominant inheritance pattern. These forms typically result from new variants in the gene and occur in people with no history of the disorder in their family.

Less commonly, collagen VI-related dystrophy is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have variants. Some cases of Ullrich congenital muscular dystrophy and the intermediate form and a few rare instances of Bethlem muscular dystrophy are inherited in an autosomal recessive manner. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Collagen VI-related dystrophy is rare. Bethlem muscular dystrophy is estimated to occur in 0.77 per 100,000 individuals, and Ullrich congenital muscular dystrophy is estimated to occur in 0.13 per 100,000 individuals. Only a few cases of the intermediate form have been described in the scientific literature.

Which doctor should you see?

The suggested department for discussing Collagen VI-related dystrophy is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Collagen VI-related dystrophy. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.